Background:Glioma therapy is challenged by the diffuse and invasive growth of glioma. Lysosomal protein transmembrane 5 (LAPTM5) was identified as an invasion inhibitor by anin vivoscreen for invasion-associated genes. The aim of this study was to decipher the function ofLAPTM5in glioblastoma and its interaction with the CD40 receptor which is intensively evaluated as a target in the therapy of diverse cancers including glioma. Methods:Knockdown ofLAPTM5was performed in different glioma cell lines to analyze the impact on clonogenicity, invasiveness, sensitivity to temozolomide chemotherapy, and tumorigenicityin vitroandin vivo. An expression array was used to elucidate the underlying pathways. CD40 knockdown and overexpression were induced to investigate a potential crosstalk ofLAPTM5and CD40.LAPTM5and CD40 were correlated with the clinical outcome of glioma patients. Results:Knockdown ofLAPTM5unleashed CD40-mediated NF kappa B activation, resulting in enhanced invasiveness, clonogenicity, and temozolomide resistance that was overcome by NF kappa B inhibition.LAPTM5expression correlated with better overall survival in glioblastoma patients depending on CD40 expression status. Conclusion:We conclude thatLAPTM5conveyed tumor suppression and temozolomide sensitation in CD40-positive glioblastoma through the inhibition of CD40-mediated NF kappa B activation. Hence,LAPTM5may provide a potential biomarker for sensitivity to temozolomide in CD40-positive glioblastoma.